Depression is the 3rd leading contributor to the global burden of disease; alcohol and illicit drug use are among the top ten contributors to that burden (World Health Organization The Global Burden of Disease: 2004 Update). In ten years of COBRE funding, the Center for Psychiatric Neuroscience (CPN) at The University of Mississippi Medical Center (UMMC) developed cutting-edge core facilities and expanded its focus to the areas of depression and alcohol dependence. Innovative and muitidisciplinary Center investigators have collaborated in ground breaking observations on the roles of neurons and glia, cerebral vasculature, aging, gender, transcription factors, serotonin and glutamate in depression and alcoholism and many have secured independent funding. Our mission in Phase III is to continue building basic research in the pathophysiology of mental illnesses and psychoactive substance use disorders by promoting mentoring, strengthening research cores and, thereby, to increase NIH funding in Mississippi. Specific Aims toward reaching this mission are to: 1) provide support to maintain and expand state-of-the-art research cores that are essential to support basic research across the institution and the state, 2) promote a collaborative and muitidisciplinary mentoring environment that supports innovative pilot research, and 3) develop a self-sustaining center of biomedical research excellence supported by investigator-initiated research grants and collaborative program projects. Our synergistic research cores, available across the institution and state-wide to other COBRE and INBRE investigators, will permit the development of mentored projects along a trajectory of using the Imaging Core and the Molecular and Genomics Core to quantify disease-specific pathology in tissues from the Postmortem Brain Core and modeling such pathology in the Animal Behavior Core to develop phenotypic models of psychopathology and explore novel treatments for depression and psychoactive substance use disorders, including alcohol dependence. State-of-the-art research cores will support mentored basic research in search of new strategies of prevention and treatment for these global challenges to mental health.